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Regioselective decarboxylative addition of malonic acid and its mono(thio)esters to 4-trifluoromethylpyrimidin-2(1H)-ones
Background: Due to the high reactivity towards various C-nucleophiles, trifluoromethylketimines are known to be useful reagents for the synthesis of α-trifluoromethylated amine derivatives. However, decarboxylative reactions with malonic acid and its mono(thio)esters have been poorly investigated so...
Autores principales: | , , , , , |
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Formato: | Online Artículo Texto |
Lenguaje: | English |
Publicado: |
Beilstein-Institut
2017
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Materias: | |
Acceso en línea: | https://www.ncbi.nlm.nih.gov/pmc/articles/PMC5727768/ https://www.ncbi.nlm.nih.gov/pubmed/29259672 http://dx.doi.org/10.3762/bjoc.13.259 |
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author | Melnykov, Sergii V Pataman, Andrii S Dmytriv, Yurii V Shishkina, Svitlana V Vovk, Mykhailo V Sukach, Volodymyr A |
author_facet | Melnykov, Sergii V Pataman, Andrii S Dmytriv, Yurii V Shishkina, Svitlana V Vovk, Mykhailo V Sukach, Volodymyr A |
author_sort | Melnykov, Sergii V |
collection | PubMed |
description | Background: Due to the high reactivity towards various C-nucleophiles, trifluoromethylketimines are known to be useful reagents for the synthesis of α-trifluoromethylated amine derivatives. However, decarboxylative reactions with malonic acid and its mono(thio)esters have been poorly investigated so far despite the potential to become a convenient route to β-trifluoromethyl-β-amino acid derivatives and to their partially saturated heterocyclic analogues. Results: In this paper we show that 4-trifluoromethylpyrimidin-2(1H)-ones, unique heterocyclic ketimines, react with malonic acid under organic base catalysis to regioselectively provide either Michael- or Mannich-type decarboxylative addition products depending on solvent polarity. Malonic mono(thio)esters give exclusively Michael-type products. The two regioisomeric products can be converted into saturated (2-oxohexahydropyrimidin-4-yl)acetic acid derivatives by mild hydrogenation of the endocyclic C=C double bond in the presence of Pd/C as catalyst. The cis-stereoisomers selectively formed upon reduction of the Michael-type products were structurally determined by X-ray diffraction. As a result of this study, a number of novel acetic acid derivatives containing trifluoromethylated, partially or fully saturated 2-oxopyrimidine cores were prepared and characterized as promising building blocks. Conclusions: Regio- and stereoselective protocols have been developed for the synthesis of novel isomeric 4(6)-trifluoromethylated 1,2,3,4-tetrahydro- and perhydro-(2-oxopyrimidin-4-yl)acetic acid derivatives. |
format | Online Article Text |
id | pubmed-5727768 |
institution | National Center for Biotechnology Information |
language | English |
publishDate | 2017 |
publisher | Beilstein-Institut |
record_format | MEDLINE/PubMed |
spelling | pubmed-57277682017-12-19 Regioselective decarboxylative addition of malonic acid and its mono(thio)esters to 4-trifluoromethylpyrimidin-2(1H)-ones Melnykov, Sergii V Pataman, Andrii S Dmytriv, Yurii V Shishkina, Svitlana V Vovk, Mykhailo V Sukach, Volodymyr A Beilstein J Org Chem Full Research Paper Background: Due to the high reactivity towards various C-nucleophiles, trifluoromethylketimines are known to be useful reagents for the synthesis of α-trifluoromethylated amine derivatives. However, decarboxylative reactions with malonic acid and its mono(thio)esters have been poorly investigated so far despite the potential to become a convenient route to β-trifluoromethyl-β-amino acid derivatives and to their partially saturated heterocyclic analogues. Results: In this paper we show that 4-trifluoromethylpyrimidin-2(1H)-ones, unique heterocyclic ketimines, react with malonic acid under organic base catalysis to regioselectively provide either Michael- or Mannich-type decarboxylative addition products depending on solvent polarity. Malonic mono(thio)esters give exclusively Michael-type products. The two regioisomeric products can be converted into saturated (2-oxohexahydropyrimidin-4-yl)acetic acid derivatives by mild hydrogenation of the endocyclic C=C double bond in the presence of Pd/C as catalyst. The cis-stereoisomers selectively formed upon reduction of the Michael-type products were structurally determined by X-ray diffraction. As a result of this study, a number of novel acetic acid derivatives containing trifluoromethylated, partially or fully saturated 2-oxopyrimidine cores were prepared and characterized as promising building blocks. Conclusions: Regio- and stereoselective protocols have been developed for the synthesis of novel isomeric 4(6)-trifluoromethylated 1,2,3,4-tetrahydro- and perhydro-(2-oxopyrimidin-4-yl)acetic acid derivatives. Beilstein-Institut 2017-12-07 /pmc/articles/PMC5727768/ /pubmed/29259672 http://dx.doi.org/10.3762/bjoc.13.259 Text en Copyright © 2017, Melnykov et al. https://creativecommons.org/licenses/by/4.0https://www.beilstein-journals.org/bjoc/termsThis is an Open Access article under the terms of the Creative Commons Attribution License (https://creativecommons.org/licenses/by/4.0), which permits unrestricted use, distribution, and reproduction in any medium, provided the original work is properly cited. The license is subject to the Beilstein Journal of Organic Chemistry terms and conditions: (https://www.beilstein-journals.org/bjoc/terms) |
spellingShingle | Full Research Paper Melnykov, Sergii V Pataman, Andrii S Dmytriv, Yurii V Shishkina, Svitlana V Vovk, Mykhailo V Sukach, Volodymyr A Regioselective decarboxylative addition of malonic acid and its mono(thio)esters to 4-trifluoromethylpyrimidin-2(1H)-ones |
title | Regioselective decarboxylative addition of malonic acid and its mono(thio)esters to 4-trifluoromethylpyrimidin-2(1H)-ones |
title_full | Regioselective decarboxylative addition of malonic acid and its mono(thio)esters to 4-trifluoromethylpyrimidin-2(1H)-ones |
title_fullStr | Regioselective decarboxylative addition of malonic acid and its mono(thio)esters to 4-trifluoromethylpyrimidin-2(1H)-ones |
title_full_unstemmed | Regioselective decarboxylative addition of malonic acid and its mono(thio)esters to 4-trifluoromethylpyrimidin-2(1H)-ones |
title_short | Regioselective decarboxylative addition of malonic acid and its mono(thio)esters to 4-trifluoromethylpyrimidin-2(1H)-ones |
title_sort | regioselective decarboxylative addition of malonic acid and its mono(thio)esters to 4-trifluoromethylpyrimidin-2(1h)-ones |
topic | Full Research Paper |
url | https://www.ncbi.nlm.nih.gov/pmc/articles/PMC5727768/ https://www.ncbi.nlm.nih.gov/pubmed/29259672 http://dx.doi.org/10.3762/bjoc.13.259 |
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